Hydroquinone derivatives and a process for their preparation

ABSTRACT

Compounds of the general formula ##STR1## wherein R represents an ether protecting group and R 3  is a group of (f)-(i) useful as intermediates.

This is a division of application Ser. No. 768,789 filed Aug. 23, 1985now U.S. Pat. No. 4,675,421.

The present invention is concerned with a novel process for themanufacture of novel hydroquinone derivatives which are useful asintermediates for the manufacture of d-α-tocopherol (natural vitamin E).The invention is also concerned with novel starting materials in thisprocess.

Several processes for the manufacture of natural vitamin E are known,but these are only of limited interest from the industrial point ofview. Accordingly, natural vitamin E has hitherto been extracted almostexclusively from natural sources. There accordingly exists a need for anindustrially realizable approach according to which natural vitamin Ecan be obtained in good yield and with high optical purity.

The process in accordance with the invention comprises

(a) reacting a compound of the general formula ##STR2## wherein Rrepresents an ether protecting group, with a ketoester of the formula##STR3## wherein R¹ represents a residue of the formula ##STR4## inwhich R² signifies phenyl, R⁴ signifies methyl or phenyl and R⁵signifies lower alkyl, aryl or aryl-lower alkyl, and, if desired,hydrolyzing a thus-obtained compound of the general formula ##STR5##wherein R and R¹ have the above significance, to a compound of thegeneral formula ##STR6## wherein R has the above significance, orreducing a compound of general formula III to a compound of the generalformula ##STR7## wherein R has the above significance, or

(b) reacting the compound of the formula ##STR8## with a compound of thegeneral formula ##STR9## wherein R has the above significance and R³represents a residue of the formula ##STR10## in which R², R⁴ and R⁵have the above significance, and, if desired, hydrolyzing athus-obtained compound of the general formula ##STR11## wherein R and R³have the above significance, to a compound of general formula IV orreducing a compound of general formula III-A to a compound of generalformula V.

The term "ether protecting group" signifies in the scope of the presentinvention not only groups which are cleavable by hydrolysis such as, forexample, the silyl group or alkoxymethyl groups, for example themethoxymethyl group, or also the tetrahydropyranyl group, but alsogroups which are cleavable oxidatively such as, for example, C₁ -C₆-alkyl ether groups.

The term "lower alkyl" signifies in the scope of the present inventionstraight-chain or branched alkyl groups with 1-6 carbon atoms such asmethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.butyl, pentyl,hexyl and the like. The term "aryl" signifies not only phenyl but alsonaphthyl which can be not only substituted but also unsubstituted. Inthe term "aryl-lower alkyl" aryl and lower alkyl have the previoussignificance.

Furthermore, in the formulae herein a solid tapering line " " indicatesthat the corresponding residue is situated above the plane of themolecule, while a series of parallel lines ".tbd." indicates that thecorresponding residue is situated below the plane of the molecule.

The compounds of formulae I, III, III-A, IV and VII are novel and arelikewise objects of the present invention.

The reaction of a compound of formula I with a ketoester of formula IIis conveniently carried out in an inert organic solvent at a temperatureof about -80° C. to about +10° C., preferably at about -20° C. to about0° C. As solvents there can be mentioned here especially those which areusually used in metal-organic reactions, especially ethers such as, forexample, diethyl ether, tert.butyl methyl ether, tetrahydrofuran and thelike.

The hydrolysis of a compound of formula III to a hydroxyacid of generalformula IV can be carried out in a manner known per se. This hydrolysisis conveniently carried out in a suitable organic solvent such as, forexample, a lower alcohol with 1-5 carbon atoms, e.g. methanol, ethanoland the like, using an alkali metal hydroxide or alkaline earth metalhydroxide, preferably sodium hydroxide or potassium hydroxide.

The reduction of a compound of formula III to a compound of formula Vcan be carried out in a manner known per se. This reduction isconveniently carried out using complex metal hydrides such as e.g.LiAlH₄, LiBH₄, diisobutylaluminium hydride and the like. As solventsthere come into consideration inert organic solvents, especially etherssuch as diethyl ether or tetrahydrofuran and the like. The temperatureand pressure at which this reduction is carried out are not critical,and accordingly the reduction can be carried out under the conditionswhich are usual for the reduction of esters to alcohols.

The ketoesters of formula II which are used as starting materials areknown compounds or analogues of known compounds which can be preparedreadily in a manner analogous to the preparation of the known compounds.The compounds of formula I which are also used as starting materialsare, however, novel and can be prepared in accordance with the followingReaction Scheme: ##STR12## wherein R has the above significance.

The conversion of the compounds of formula VIII into the Grignardcompounds of formula IX can be carried out under the conditions whichare usual for the preparation of Grignard compounds.

The reaction of a Grignard compound of formula IX with the compound offormula VI-A can be carried out in a manner known per se. This reactionis conveniently carried out at about -80° C. to about 0° C., preferablyat -20° C. As solvents there can be used all solvents which also comeinto consideration in the preparation of Grignard compounds.

The reaction of the compound of formula VI with a compound of formulaVII can be carried out in a manner known per se, especially in a manneranalogous to the reaction of a compound of formula I with a ketoester offormula II.

The compound of formula VI which is used as the starting material isknown. The compounds of formula VII which are also used as startingmaterials are, however, novel and are likewise an object of the presentinvention. They can be prepared as illustrated in the following Scheme.##STR13## wherein R, R², R⁴ and R⁵ have the above significance.

The reaction of a compound of formula X with pyruvic acid can be carriedout in a manner known per se. This reaction is conveniently carried outin an aqueous-alcoholic medium with the addition of a base such as, forexample, potassium hydroxide or sodium hydroxide. The reduction of acompound of formula XI to a compound of formula XII can also be carriedout in a manner known per se, preferably catalytically in the presenceof a base. As the catalyst there can be used, in particular, palladium.As bases there can be used inorganic bases such as sodium hydroxide orpotassium hydroxide or also organic bases such as triethylamine and thelike.

The reaction of a compound of formula XII with a compound of formulaeXIII-A to XVIII-A can be carried out in a manner which is usual for thepreparation of esters from acids and alcohols. The esterification ispreferably carried out by firstly converting the acid into theimidazolide and then reacting this with the alcohol.

The compounds of formulae IV and V which are manufactured in accordancewith the invention are valuable intermediates in the synthesis ofnatural vitamin E.

The compounds of formula IV can be converted, for example, into theknown compound of the formula ##STR14## and this can be converted in amanner known per se into natural vitamin E. The conversion of thecompounds of formula IV into the compound of formula XIX can be carriedout in a manner known per se. This conversion is conveniently carriedout by oxidation using Ce(NH₄)₂ (NO₃)₆ in aqueous acetonitrile.

The compounds of formula V can be converted into natural vitamin E, forexample, by converting the compounds of formula V into epoxides,reacting the resulting epoxides of the general formula ##STR15## whereinR has the above significance, with the Grignard compound of the generalformula ##STR16## and converting the thus-obtained known compounds ofthe general formula ##STR17## wherein R has the above significance, intod-α-tocopherol in a known manner.

The conversion of a compound of formula V into an epoxide of formula XXcan be carried out in a manner known per se. For this purpose, theprimary hydroxy group in a compound of formula V is firstly convertedinto a leaving group, e.g. into a halide (chlorine, bromine and iodinecoming into consideration as the halogen) or into a sulphonic acid ester(e.g. tosylate or mesylate) and the like. This can be carried out in amanner known per se. The thus-obtained compound is subsequently treatedwith a base. As bases there are suitable not only inorganic bases butalso organic bases, preferably inorganic bases such as especially sodiumhydroxide or potassium hydroxide and the like.

The reaction of an epoxide of formula XX with the Grignard compound offormula XXI can be carried out in a manner known per se. However, it ispreferred to carry out the reaction in the presence of copper(I or II)catalysts, especially copper(I)-n-propylacetylide or a copper(I)halide-dimethyl sulphide complex. As solvents for this reaction thereare suitable all solvents which usually come into consideration inGrignard reactions.

The compounds of general formula XXII are known and can be convertedinto d-α-tocopherol in a known manner.

EXAMPLE 1

A solution of 18.6 mmol of2-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-ethyl triisopropoxytitaniumin 20 ml of tetrahydrofuran is treated dropwise at -20° C. whilestirring with 3.12 g (10.3 mmol) of (-)-8-phenylmenthyl pyruvate and themixture is subsequently left to stand at -20° C. for a further 16 hours.After the addition of 50 ml of aqueous sodium dihydrogen phosphatesolution (10%) the mixture is extracted three times with 50 ml of ethereach time. The combined organic phases are dried over sodium sulphateand the solvent is then removed on a rotary evaporator. There areobtained 6.76 g of (-)-8-phenylmenthyl(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoate.

The 2-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-ethyltriisopropoxytitanium which is used as the starting material can beprepared as follows:

5.34 g (18.6 mmol) of1-(2-bromoethyl)-2,5-dimethoxy-3,4,6-trimethylbenzene are heated atreflux for 1 hour in 20 ml of dry tetrahydrofuran with 0.50 g (20.8mmol) of magnesium. 4.71 ml (19.0 mmol) of chloro-triisopropoxy-titaniumare then added at -20° C. The solution of the resulting2-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-ethyl triisopropoxytitaniumis processed directly.

EXAMPLE 2

A solution of 0.907 g (about 1.35 mmol) of (-)-8-phenylmenthyl(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoatein 10 ml of ethanol is treated with 1 ml of 28% sodium hydroxidesolution and the mixture is left to stand at room temperature for 16hours. The mixture is then diluted with 50 ml of water and extractedthree times with 50 ml of ether each time. The aqueous phase isacidified (pH 2) with 10% phosphoric acid and extracted three times with50 ml of ether each time. The combined organic phases are dried oversodium sulphate and the solvent is subsequently removed on a rotaryevaporator. There are obtained 212 mg of(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoicacid.

EXAMPLE 3

A solution of 6.76 g (about 10.3 mmol) of (-)-8-phenylmenthyl(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoatein 50 ml of dry ether is added dropwise while stirring to a suspensionof 0.380 g (9.98 mmol) of LiALH₄ in 10 ml of ether. After stirring atroom temperature for a further 2 hours 10 ml of ethyl acetate are addeddropwise (decomposition of excess LiAlH₄) and subsequently 10 ml of 10%aqueous sodium dihydrogen phosphate solution are added dropwise. Thereaction mixture is extracted three times with 50 ml of ether each time,the combined organic phases are dried over sodium sulphate and thesolvent is removed on a rotary evaporator, whereby 4.61 g of crude(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediolare obtained. The crude product is reprecipitated from 10 ml of etherand 40 ml of hexane and gives 1.68 g of the pure diol as a whiteproduct.

M.p. 85°-86° C.; [α]_(D) ²⁵ =+2.79° (c=2% in chloroform).

In the ¹ H-NMR (60 MHz) using Eu(HFC)₃ as the chiral shift reagent thecompound, as the acetonide, is found to be optically pure (e.e. >90%).

EXAMPLE 4

A solution of 0.78 mmol of2-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-ethyl triisopropoxytitanium(prepared according to Example 1) in 10 ml of dry tetrahydrofuran istreated while stirring at -20° C. with 0.30 g (0.95 mmol) of(+)-cis-3-benzylbornyl pyruvate and the mixture is subsequently left tostand at -20° C. for a further 16 hours. The working-up is carried outin a manner analogous to that described in Example 1 and there isobtained (+)-cis-3-benzylbornyl(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoatewhich is saponified directly in a manner analogous to that described inExample 2. The aqueous phase which is thereby obtained is treated with0.5 ml of dimethyl sulphate and 20 mg of Aliquat 336 (a phase transfercatalyst from the firm Fluka/CH) and the mixture is stirred at roomtemperature for 1 hour. 1 ml of 25% ammonia is added and the resultingmixture is stirred at room temperature for a further 1 hour (removal ofexcess dimethyl sulphate). By extracting the reaction mixture withether, drying the ether phase over sodium sulphate and removing thesolvent there are obtained 150 mg of methyl(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoate.Optical purity according to HPLC on a "Pirkle Phase"=95% e.e.

The (+)-cis-3-benzylbornyl pyruvate which is used as the startingmaterial can be prepared as follows:

A solution of 0.88 g (10 mmol) of pyruvic acid in 20 ml of dry methylenechloride is treated with 2.2 g (10 mmol) of carbonyldiimidazole and themixture is stirred until the evolution of gas has finished (about 10minutes). To the thus-obtained solution of pyruvic acid imidazolidethere are added 3.7 g (10 mmol) of (+)-cis-3-benzylborneol in drymethylene chloride together with 1 mmol of imidazole lithium as thecatalyst. The mixture is stirred overnight at room temperature,subsequently taken up with water and ether, the ether phase is filteredthrough silical gel, the filtrate is concentrated and the residue isdistilled in a high vacuum (10⁻² Torr) at about 190° C. There areobtained 4.5 of (+)-cis-3-benzylbornyl pyruvate. Thin-layerchromatography: (silica gel; toluene/ethyl acetate 10:1): Rf=0.4.

EXAMPLE 5

A solution of 1.4 g (2.68 mmol) of (-)-cis-3-benzylbornyl4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-ketobutanoate in 20 ml ofdry tetrahydrofuran is treated while stirring at -20° C. with 3 mmol ofmethyl-triisopropoxytitanium in 1 ml of hexane and this mixture issubsequently left to stand at -20° C. for a further 16 hours. Theworking-up is carried out in a manner analogous to that described inExample 1 and there is obtained (-)-cis-3-benzylbornyl(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoatewhich is converted into the methyl ester in a manner analogous to thatdescribed in Example 4.

Optical purity according to HPLC on a "Pirkle Phase": 70% e.e. Theoptical purity of the (-)-borneol originally used was also 70% e.e.

The experiment carried out with optically pure (+)-borneol in a manneranalogous to the foregoing gave the corresponding (R)-methyl ester withan optical purity of 95% e.e.

The (-)-cis-3-benzylbornyl4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-ketobutanoate which isused as the starting material can be prepared starting from4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-ketobutanoic acid and(-)-cis-3-benzylborneol in a manner analogous to that described inExample 4.

The aforementioned4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-ketobutanoic acid can beprepared as follows:

A suspension of 3.7 g (17.6 mmol) of2,5-dimethoxy-3,4,6-trimethylbenzaldehyde and 5.0 g (53.2 mmol) ofsodium pyruvate in 20 ml of methanol is treated with 0.1 g (1.8 mmol) ofpotassium hydroxide and the mixture is subsequently heated at reflux for5 hours, whereby a yellow solution is obtained. The reaction mixture ispoured on to ice-water and the resulting4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-keto-3-butenoic acid isprecipitated by the addition of sulphuric acid while stirring. Thesuspension is stirred for 1 hour, filtered, the filter residue is washedwith water and dried. In this manner there are obtained 4.9 g of4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-keto-3-butenoic acid inthe form of a yellow powder of melting point 126°-127° C.

1.02 g (3.5 mmol) of this powder in 80 ml of water are hydrogenated over400 mg of Pd/C (5%) under normal pressure with the addition of 10 ml of1N sodium hydroxide solution until the control by thin-layerchromatography indicates complete hydrogenation. The catalyst isfiltered off, the filtrate is acidified to pH 4 with phosphoric acid andextracted with ether. By evaporation of the ether extracts, dried oversodium sulphate, there is obtained 0.75 g of4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-ketobutanoic acid.

EXAMPLE 6

In a manner analogous to that described in Example 5,(1S)-1-benzylcarbamyl-ethyl4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-ketobutanoate is reactedwith methyl-triisopropoxytitanium firstly at -78° C. for 5 hours andthen at -20° C. for 16 hours and the reaction product is then convertedinto the methyl ester. The optical purity is above 95% e.e. according toHPLC on a "Pirkle Phase".

The (1S)-1-benzylcarbamyl-ethyl4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-ketobutanoate which isused as the starting material can be prepared from4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-ketobutanoic acid and(1S)-1-(benzylcarbamyl)ethanol (=L-lactic acid benzylamide) in a manneranalogous to that described in Example 4.

EXAMPLE 7

148 mg (0.5 mmol) of(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-hydroxy-2-methylbutanoicacid (prepared according to Example 2) are dissolved in 2 ml ofacetonitrile, the solution is treated while stirring with 560 mg (1mmol) of Ce(NH₄)₂ (NO₃)₆ in 2 ml of water and the mixture issubsequently stirred at room temperature for a further 10 minutes. Themixture is then treated with 50 ml of water and extracted three timeswith 50 ml of chloroform each time. After drying over sodium sulphatethe combined organic phases are concentrated and there are thus obtained111 mg of(+)-(S)-2-hydroxy-2-methyl-4-(2',4',5'-trimethyl-3',6'-dioxo-1',4'-cyclohexadien-1'-yl)butanoicacid.

M.p. 115°-117° C.; [α]_(D) ²⁵ =+11° (c=0.2% in chloroform); opticalpurity of the educt according to HPLC on a "Pirkle Phase" 95% e.e.

The product which is obtained after catalytic reduction and subsequentacidic cyclization, i.e.(-)-(S)-6-hydroxy-2,5,7,9-tetramethylchromane-2-carboxylic acid, isobtained optically pure after recrystallization from toluene.

[α]_(D) ²⁵ =-68.8° (c=1% in chloroform).

EXAMPLE 8

(a) 237 mg of tosyl chloride and 350 mg of(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediolare dissolved in 1 ml of methylene chloride. 0.180 ml of pyridine arethen added dropwise at 0° C. and the mixture is left to stand at 0° C.for 1 hour and then at room temperature for 16 hours. Thereupon, 1 g ofice and 0.3 ml of concentrated hydrochloric acid are added. The mixtureis then extracted with methylene chloride, and the extract is dried andconcentrated. There are obtained 511 mg (95%) of(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1-toluenesulphonyloxy-2-butanol.

[α]_(D) ²⁰ =+1.2° (c=2.6% in chloroform).

(b) 177 mg of(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1-toluenesulphonyloxy-2-butanolare dissolved in 1 ml of ethanol and the solution is treated with 0.3 mlof alcoholic sodium hydroxide solution (1.5N). The mixture is left tostand at room temperature for 10 minutes, 30 ml of methylene chlorideare then added and the mixture was dried over sodium sulphate andconcentrated. There are obtained 105 mg of(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxybutane.M.p. 47°-48° C.

[α]_(D) ²⁰ =+4.91° (c=2.2% in chloroform).

(c) 5.8 mmol of (3R,7R)-3,7,11-trimethyldodecyl bromide are heated atreflux for 1/4 hour in 20 ml of ethyl acetate with activated magnesium.Then, there are added at 0° C. 1 g of(S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxybutaneand 0.9 g of copper(I)-2-propylacetylide [or 1.2 g of copper(I)bromide/dimethyl sulphide complex]. The temperature of the reactionmixture is subsequently left to rise to room temperature and the mixtureis stirred overnight. 10 ml of ammonium chloride are than added and themixture is extracted with ethyl ether. The extract is dried andconcentrated, and the residue is distilled in a bulb-tube (b.p.₀.01=140° C.). There are obtained 1.28 g (72%) [or 1.41 g (79%)] of(3R,7R,11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-3,7,11,15-tetramethylhexadecan-3-olas a colourless oil.

[α]_(D) ²⁰ =-0.67° (c=0.9% in chloroform).

C₃₁ H₅₆ O₃ (476.79) Calc.: C=78.09 H=11.84. Found: C=77.92 H=11.88.

We claim:
 1. Compounds of the general formula ##STR18## wherein R and R³have the significance wherein R represents an ether protecting group;and R³ represents a residue of the formula ##STR19## in which R²signifies phenyl; R⁴ signifies methyl or phenyl and R⁵ signifies loweralkyl, aryl or aryl-lower alkyl, wherein aryl signifies phenyl andnaphthyl.
 2. Compounds according to claim 1 wherein the ether protectinggroup signifies silyl group, lower alkoxymethyl group, tetrahydropyranylgroup or C₁ -C₆ alkyl.